The leukotrienes are potent inflammatory mediators which may have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowel disease and asthma. Biosynthetically, generation of leukotrienes is catalyzed by the calcium and ATP-dependent enzyme 5-lipoxygenase, which metabolise arachidonic acid via the insertion of oxygen moiety at a specific position, into hydroperoxyeicosatetraenoic acids (HPETEs). LTB4, LTC4, LTD4, LTE4 and the cysteinyl leukotrienes (CysLTs) are the clinically important leukotrienes. To synthesize leukotrienes, cells need 5-lipoxygenase and a protein co-factor 5-lipoxygenase activating protein (FLAP) and drugs that act on either of the two inhibit their synthesis and actions. There are two distinct receptor types for the CysLTs (CysLT1 and CysLT2 receptors) and one for LTB4 (BLT receptor). LTB4 is a potent chemotactic agent and attracts pro-inflammatory cells, e.g. eosinophils, into tissues. The CysLTs contract airway and some vascular smooth muscle, stimulate mucus secretion and increase micro vascular permeability. Further details of the leukotrienes are to be found in the book “Leukotrienes and Lipoxygenase”, ed. J. Rokach, Elsevier, Amsterdam (1989). Rokach also discusses the actions of the leukotrines in living systems and their contribution to various disease states in the book. Montelukast Sodium being a leukotriene antagonist is useful in the treatment of pulmonary disorders including asthma and related obstructive airway diseases, allergies and allergic reactions, inflammation as well as anti-inflammatory agent, skin disorders, cardiovascular disorders, cerebral disorders, uveitis, glomerular, nephritis, hepatitis, and allograft rejection.
Montelukast sodium is chemically described as [R-(E)]-1-[[[1-[3-[2-(7-Chloro-2-quinolinyl ethenyl]phenyl]-3-[2-[(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl] cyclopropane acetic acid, sodium salt and is known to be a therapeutically useful compound. Its empirical formula and molecular weight are C35H35CINNaO3S and 608.17 respectively. Montelukast sodium displays the structural formula (I). It is a optically active, highly hygroscopic, white to off-white powder, freely soluble in ethanol, methanol and water and practically insoluble in acetonitrile.

Synthesis of Montelukast sodium in its amorphous form (Process A—Scheme 1) is fully described by reference to the examples, in U.S. Pat. No. 5,565,473 and European Patent Publication 0, 480, 717.
Synthetic Scheme for Preparing Amorphous Montelukast Sodium as per U.S. Pat. No. 5,565,473

The reported synthesis of (I) proceeds through its corresponding methyl ester (V) whose formation comprises sodium hydride or cesium carbonate assisted coupling of methyl-1-(mercaptomethyl)cyclopropaneacetate (III) with the protected mesylate of formula (II) to afford the protected alcohol ester derivative (IV) followed by its deprotection under acidic conditions. The ester (V) is hydrolyzed to free acid (VI) and then converted directly to sodium salt (I). According to the examples of above cited patents, montelukast acid (VI) in its pure form is first treated with sodium hydroxide in ethanol, the solvent is evaporated under vacuum, the resulting viscous oil is dissolved in water and then freeze-dried. Pure (VI) used was obtained via the hydrolysis of corresponding ester (V) with methanolic sodium hydroxide followed by acidification with dilute acetic acid and finally purified through time consuming column chromatography on silica gel. The process is obviously lengthy as well as tedious since it requires chromatographic purification of both the methyl ester (V) and montelukast acid (VI). Further, it also requires capital-intensive freeze-drying equipment and thus proves to be commercially expensive if not unviable.
As indicated above, the reported syntheses of montelukast acid (VI) proceeds through its corresponding methyl ester (V) and involves coupling of methyl-1-(mercaptomethyl) cyclo propane acetate (III) with a mesylate (II) generated in situ. The methyl ester (V) thus obtained is hydrolyzed to the free acid (VI), which in turn is converted directly to the corresponding sodium salt. The process is not suitable for large-scale production, as it requires tedious chromatographic purification of intermediates and freeze-drying of Montelukast sodium (I).
Moreover, the yields of the intermediates are also low.
U.S. Pat. No. 5,614,632 advocates the preparation of Montelukast sodium in crystalline form. As per detailed description, the process comprises converting 1-(mercaptomethyl) cyclopropaneacetic acid into dilithium dianion by reacting with lithium bases such as n-butyl lithium in hexane or heptane in presence of inert solvents like tetrahydrofuran (THF), toluene, or mixture thereof at sub-zero temperatures and then reacting the said dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid with the mesylate in solid or solution form, in inert organic solvents such as THF or toluene, preferably THF.
The mesylate has limited stability in solution and is therefore preferably prepared just prior to the reaction with the dianion solution. It is isolated in solid form at low temperature and stored at −15° C. over a period of time. The solution can best be used within about 30 minute of its preparation. Optionally, during its preparation, the reaction mixture is seeded with the crystals of mesylate in order to accelerate crystallization of the product. Further, in accordance with the example, the process leads to selective mono mesylation of diol with methanesulphonyl chloride in the presence of sterically hindered base N,N-diisopropylethylamine in a mixture of toluene and acetonitrile. After the addition of methanesulphonyl chloride, the reaction mixture is seeded with crystals of previously prepared mesylate salt to induce crystallization as stated above. The mesylate after careful filtration under nitrogen gas atmosphere at −25° C. is washed successively with chilled acetonitrile (−30° C.) and hexanes (+5° C.) and then dried at +5° C. by passing dry nitrogen gas through it for approximately 20 hrs. This is a risky process requiring capital intensive cold room facility, constant careful handling as accidental rise in temperature during this lengthy drying procedure could either lead to the formation of impurities which may be carried forward to the next stage or result in complete decomposition of the expensive advanced intermediate. The dried mesylate is then coupled with the dianion generated from 1-(mercaptomethyl)cyclopropaneacetic acid and n-butyl lithium (15% solution in hexanes) at −5±2° C. in THF to obtain after workup and recovery of solvents, Montelukast acid in crude form, as a viscous oil. The reaction between dianion and mesylate is allowed to take place at subzero temperatures for about 10 hrs followed by treatment of the reaction mixture with a carboxylic acid, preferably tartaric acid to produce montelukast acid in crude and impure form. The crude acid thus obtained has to be purified through its corresponding salt dicyclo hexyl amine salt (DCHA) produced by reacting the said acid with DCHA in presence of solvent to facilitate crystallization
Depending upon the solvent used, two crystalline forms of the DCHA salt are obtained. Form A is crystallized from a mixture of ethyl acetatehexanes and Form B from toluene/heptane. The montelukast DCHA salt, after filtration has to be washed with in a mixture of toluene/n-heptane or ethyl acetate/n-hexane before being converted into crystalline Montelukast sodium (I). The examples also advise seeding with crystals of DCHA salt to accelerate crystallization of the product.
The process as described, teaches that the dicyclohexylamine (DCHA) salt is readily isolable in crystalline form and is advantageously used as means of purification of title product of the invention. The montelukast acid, generated in-situ in toluene, by treating DCHA salt with dilute acetic acid is directly converted into montelukast sodium by reacting with sodium hydroxide and after repeated recovery of solvents is crystallized (after seeding with the difficult to obtain crystals) by slowly adding excess of acetonitrile to the toluene solution at +40±2° C. After the addition of acetonitrile, the slurry of crystalline montelukast sodium is aged for 12 to 16 hrs at +40±2° C. In order to obtain montelukast sodium in pure and crystalline form, the DCHA salt (X) with purity ≧99% is used and seeding plays a very critical role during crystallization.
As is clear from the above discussions, both the routes (Processes A and B) for the synthesis of montelukast sodium suffer from several drawbacks and involve steps that are lengthy, tedious, non-reproducible and require stringent conditions and high capital infrastructure. Additionally, they require intermediates of high purity, which may have to be chromatographically purified. Therefore, there is a need for developing methodologies, which overcome the above mentioned drawbacks.